Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity

Steri, Ramona; Achenbach, Janosch; Steinhilber, Dieter; Schubert‐Zsilavecz, Manfred; Proschak, Ewgenij

doi:10.1016/j.bcp.2012.02.027

Cited by 33 publications

(31 citation statements)

References 37 publications

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“…The slightly more polar 3,4-methylenedioxobenzoyl residue (34) in place of the lipophilic 2-naphthoyl group diminished activity on all PPARs and FXR while the smaller 3-fluoro-4-trifluoromethylbenzoyl moiety in 35 as a minimal naphthoyl analogue showed comparable PPAR agonistic activity as 30 while its activity on FXR was diminished. When the substitution pattern was moved from a 3,4-disubstitution in 35 to a 3,5-disubstitution in 36, activity on all PPARs and FXR was diminished.…”

Section: Structure-activity Relationshipmentioning

confidence: 80%

“…Plasmids for full length FXR transactivation assay pcDNA3-hFXR contains the sequence of human FXR and was already published elsewhere [34], pGL3basic (Promega, Mannheim, Germany) was used as a reporter plasmid, with a shortened construct of the promotor of the bile salt export pump (BSEP, sequence of construct from [35]) cloned into the SacI/NheI cleavage site in front of the luciferase gene. pRL-SV40 (Promega) was transfected as a control for normalization of transfection efficacy and cell growth.…”

Section: Cell Culturementioning

confidence: 99%

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Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Merk

Lamers

Wéber

et al. 2015

Bioorganic & Medicinal Chemistry

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Section: Structure-activity Relationshipmentioning

confidence: 80%

Section: Cell Culturementioning

confidence: 99%

Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Merk

Lamers

Wéber

et al. 2015

Bioorganic & Medicinal Chemistry

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“…Results from a preclinical murine model strongly suggested that this may be mediated through PDGFR, and to a minor extent c‐KIT inhibition . More recently, chemical structure analysis suggests an additional mechanism of imatinib acting as a ligand to modulate farnesoid X receptor (FXR), a transcription factor belonging to the nuclear receptor superfamily that is involved in glucose and lipid homeostasis . Thus, diabetic patients who are prescribed these medications should monitor blood glucose routinely as dose reduction or discontinuation of their antihypoglycemic regimen maybe required to avoid symptomatic hypoglycemia.…”

Section: Mechanism‐based Toxicitiesmentioning

confidence: 99%

Understanding, recognizing, and managing toxicities of targeted anticancer therapies

Adjei

2013

CA A Cancer J Clinicians

280

205

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Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed.

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“…[7,8] Along with the fact that significant progress has been made in cancert herapy,i matinib has also been used in countless experimental in vitro and in vivo studies. [9][10][11][12] Considering the prominent role of this multi-kinase inhibitor in signal-transduction analysis,i tw ould be beneficial to develop ap hotoactivatable imatinib prodrug. Therefore, we aimed to provide as o-called caged compound that can be activated by irradiation with ultraviolet (UV) light.…”

mentioning

confidence: 99%

Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib

et al. 2015

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Imatinib is the first protein kinase inhibitor approved for clinical use and is a seminal drug for the concept of targeted therapy. Herein we report on the design, synthesis, photokinetic properties, and in vitro enzymatic evaluation of a photoactivatable caged prodrug of imatinib. This approach allows spatial and temporal control over the activation of imatinib triggered by ultraviolet light. The successful application of the photoactivation concept to this significant kinase inhibitor provides further evidence for the caging technique as a feasible approach in the kinase field. The presented photoactivatable imatinib prodrug will be highly useful as a pharmacological tool to study the impact of imatinib toward biological systems in greater detail.

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Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity

Cited by 33 publications

References 37 publications

Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Anthranilic acid derivatives as nuclear receptor modulators—Development of novel PPAR selective and dual PPAR/FXR ligands

Understanding, recognizing, and managing toxicities of targeted anticancer therapies

Design, Synthesis, and Characterization of a Photoactivatable Caged Prodrug of Imatinib

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